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International Journal of Pharmacy Teaching & Practices 2012, Vol.3, Issue 4, 429-433. Role of Bisoprolol Adding oo Ace Inhibitor and Fu rosemide Combination on the Left
Ventr icular Function in Systolic Heart Failure Patients
Efta T riastuti 1*, Dadang Hendrawan2, Muha
mmad Saifurrohman 3
1Study Program of Pharmacy, Faculty of Medicine, Braw ijaya University, Malang, Indonesia 2,3Cardiovascular Department, Dr. Saiful Anwar Hospital, Malang, Indonesia Introduction
Research Article
Heart failure is defined as clinical syndromes (such Please cite this paper as: Efta Triastuti 1*, Dadang Hendrawan2, as: short of breathing, activities limitation, or Muhammad Saifurrohman 3. Role of Bisoprolol Adding oo Ace pulmonary obstruction) manifest from degradation Inhibitor and Furosemide Combination on the Left Ventricular Function in Systolic Heart Failure Patients.
of heart function caused by various heart diseases. This syndrome may lead to quality of life reduction Corresponding Author:
with higher morbidity and mortality than other Efta Triastuti
Study Program of Pharmacy, Faculty of Medicine, Brawijaya American Heart Association guideline of heart failure recommend β-blocker combined with ACE Inhibitors and diuretics as an established therapeutic strategy for stage C systolic heart failure patients throughout contraindications are not found. Previous study Abstract
found that this brought many benefits in morbidity and mortality if given to stabile heart failure Background: β-blocker is an established therapeutic strategy
patients4,5,6. In contrary, not many physicians for stage C systolic heart failure based on the American Heart confidence to prescribe β-blocker to the heart Association guideline, nonetheless limited studies analyzed the role of β-blocker primarily Bisoprolol adding to ACE inhibitor and furosemide combination on the left ventricular function in β-blocker inhibits the surge of β adrenergic activity. The surge of β adrenergic activity in heart failure wil Objectives: This study was designed to analyze the role of
Bisoprolol adding to ACE inhibitor and furosemide vasocontriction, sodium and water retention which combination on the ventricular function in patients with lead to increase cardiac load and aggravate systolic heart failure particularly on ejection fraction and hypoperfusion due to inadequate ventricular ejection. β-blocker act to decrease heart rate and Subjects & Methods: 40 to 80 years old ambulatory patients
prolonged the ventricular fil ing time, then provide (N=30) at Dr. Saiful Anwar General Hospital Malang diagnosed adequate preload at diastolic phase and improve as stage C systolic heart failure receiving optimum dose of inhibitor ACE and furosemide combination for at least 2 months. Before Bisoprolol was added, the ejection fraction Bisoprolol is one of selective β-blocker that available and the quality of life was observed to assess the baseline left in indonesia. It has prominently high β1 affinity, low ventricular function then re-observed after 3 months. bronchoconstriction effect, and it has no intrinsic Results: After the adding of Bisoprolol, there were significant
simphatomimetic activity (high bradycardia effect) differences in ejection fraction (measured by and membrane stabileity activity therefore has echocardiography) and quality of life (measured by Minnesota minimum effect on cardiac conductance3,12. quality of life living with heart failure questionnaire) with both The aim of this study is to analyze the role of P value equal to 0,000 (95% Confidence Interval). Bisoprolol adding to ACE inhibitor and furosemide Conclusions: The adding of Bisoprolol to ACE inhibitor and
combination on the ventricular function in patients Furosemide combination seems to improve the left ventricular with systolic heart failure particularly on ejection function in stage C systolic heart failure patients particularly on ejection fraction and quality of life measurements. Keywords: heart failure, Bisoprolol, ejection fraction,
echocardiography, quality of life International Journal of Pharmacy Teaching & Practices 2012, Vol.3, Issue 4, 429-433. Material and Method
differences in distribution, with the P value for those are > 0.05. Comorbid condition (previous disease Research was conducted in Dr. Saiful Anwar General Hospital history) categorized in to three group then examined Malang, Indonesia between february 2011 to january 2012. by Chi-Square analysis and resulted P = 0.061. Chi- This quasi-experimental study used a one group pretest- Square analysis also conducted to determine the age posttest design to compare the ejection fraction (by (divided in to four groups in table 1) and gender echocardiography) and quality of life (by Minessota Living with differences and resulted P value 0.141 and 0.465 Heart Failure questionnaire) measurements before and after respectively. Patients demographic data summarized the adding of Bisoprolol to ACE inhibitor and furosemide combination for three months at stage C systolic heart failure TABLE 1. Patients Demographic Data
40 – 80 years of age stage C systolic heart failure patients with EF reduction were included. Inclusion criterias were stabile heart failure, already received the optimum dose of ACE inhibitor and furosemide, fulfil for Bisoprolol indication. Patients were excluded if already accepted Bisoprolol before recruitment, had acute heart failure and needed positive inotropic except digoxin, comorbid condition which affect to quality of life such as mitral regurgitation and atrial fibrilation, cardiogenic shock, bradycardia (heart rate below 60 times per History of previous illness:
minute), hypotension with systolic pressure below 100 mmHg, Ejection fraction measured by two operator using echocardiography with Simpson method of measurement as a EJECTION FRACTION (EF)
gold standard. Minessota Living with Heart Failure EF show the fraction of blood that ejected from the Questionnaire is already used worldwide to measure the left ventricle. Normal value of EF is in the range quality of life of heart failure patients. between 53% to 72% while in heart failure EF may reduce to 50% or below. Lowest EF value at baseline This study examined the ambulatory patients of Cardiovascular was 17% while at endpoint was 24%. Highest EF Department at Dr. Saiful Anwar General Hospital Malang. value at baseline was 49% while at endpoint was Patient adherence has significant contribution to the result of this study, thus this study enclosed to the high adherence patients (measured by patients adherence questionnaire). Normality test for EF showed that endpoint EF data did not meet Gaussian distribution so that data DATA ANALYSIS
analysis should used nonparametric test for two EF and quality of life are dependent variables measured in this related samples that is Wilcoxon Signed Ranks Test. study. Both variables show the left ventricular function. Wilcoxon Signed Ranks Test results showed that Baseline EF and quality of life were compared to those results baseline EF were significantly differ from endpoint three months after Bisoprolol addition using paired t test EF with P value equal to 0.000 (95% Confidence analysis in the Statistical Product and Service Solutions (SPSS) Interval (CI); 0.00 to 0.27). Wilcoxon test results for version 16. Normal distribution data is required for Paired t test as a parametric analysis. This is examined by Shapiro-Wilk analysis for smal size sample (below 50). Wilcoxon analysis is TABLE 2. Wilcoxon Test Results for EF
the alternate analysis to compare baseline EF and quality of EF percentage (%)
life to the endpoint if the data do not fulfil normal distribution. Mean baseline
Mean at 3rd months
Total patients who meet inclusion and exclusion criteria EF mean at baseline and 3rd months comparison by between february to October 2011 were 30 patients fol owed Wilcoxon test was displayed to the bar charts in up for three months with the endpoint measurements last on January 2012. Chi-square statistical test using SPSS 16 carried out to see the distribution of patient demographic data. Sex, age, and previous disease history respectively did not show significant International Journal of Pharmacy Teaching & Practices 2012, Vol.3, Issue 4, 429-433.
TABLE 3. Paired t Test Results for Sum Score of
Minessota Living with Heart Failure
Sum Score of
Minessota Living
with Heart Failure
Mean baseline
Mean at 3rd months
Figure 1. Profile of Baseline Mean Ejection Fraction Compared
to Those after the Adding of Bisoprolol for Three Months
QUALITY OF LIFE
Quality of life for heart failure patients measured by Minessota
Living with Heart Failure questionnaire. This questionnaire
consists of twenty one questions each questions contain six
choices based on the symptoms frequencies which is valued 0,
1, 2, 3, 4, 5 respectively. The more frequent symptoms would
provide the higher score for this questionnaire. The maximum
score of this questionnaire is 105, which is explained that the
heart failure condition has a very high impact to the reduction
of quality of life.
Quality of life data taken from the the patients based on the Figure 2. Profile of Mean Score of Minessota Living
questionnaire results in this study showed that the highest with Heart Failure Questionnaire Comparison score of Minessota Living with Heart Failure Questionnaire was 70 at baseline and 64 after three months receiving Bisoprolol. Discussion
While the lowest score for this questionnaire was 37 at Background setting in this study was conducted at baseline and 30 at the endpoint after the adding of Bisoprolol ambulatory clinic in cardiovascular department, Dr Saiful Anwar General Hospital, Malang. Since recruited samples were ambulatory patients, many Normality test for patients quality of life showed that the counfounding factor may had significant impact on distribution data met Gaussian distribution (normal the results. One of the method to minimize the distribution) so that data analysis should used parametric test effect of confounding factor to the results was by for two related samples that is Paired t test. limiting sample recruitment only to the adherence Paired t test results showed that the baseline quality of life questionnaire score were significantly differ from endpoint Other confounding factors were gender, comorbid score with P value equal to 0.000 (95% Confidence Interval condition (history of previous chronic il ness), and (CI); -18 to -1). Paired t test results for quality of life age. Thus Chi-Square analysis conducted to questionnaire score summarized in table 3. determine whether those factors impact to the examined variables such as ejection fraction and Mean of Minessota Living with Heart Failure score at baseline quality of life. Chi-Square analysis resulted that and 3rd months comparison by Paired t test was displayed to demographic data taken from the patients were equivalent thus no classification based on gender, comorbid condition, and age were needed in International Journal of Pharmacy Teaching & Practices 2012, Vol.3, Issue 4, 429-433. Previous studies (CIBIS I, II, III) demonstrated the improvement after contraction phase this wil aggravate the left in morbidity, mortality and length of hospitalization stay in heart failure patients who were treated with Bisoprolol. While previous studies did not analyze the role of Bisoprolol to the EF can be measured by several methods. The best left ventricular function, this study primarily examined the left method which used to be a gold standard is Simpson ventricular function due to ejection fraction and quality of life. method. This method calculates the left ventricular This study resulted that there were significantly improvement volume in the end of diastolic and systolic phase in left ventricular function which were shown in the increasing then develope to the formula above. This method of ejection fraction (P = 0.000) and decreasing score of quality minimize the operator error in determine the cut of life questionnaire (P = 0.000). This result probably delivered point of the left ventricle. This study recruited two by the reduction of cardiac oxygen demand as a result from blinded operator to examine the ejection fraction to the decreasing of heart rate so that ischemic related symptom improved. Other mechanism of Bisoprolol in improving left ventricular function was due to the antagonistic effect of Baseline ejection fraction from the patients then aldosteron by inhibits renin release so that decreasing in water compare to themselves ejection fraction after and sodium retention which bring to the reduction of cardiac receiving Bisoprolol for three months. Comparison load and decrease ischemic state9,10,13. method was by Wilcoxon test since the baseline ejection fraction showed non Gaussian distribution. This study conducted a quasi-experimental with one group As the results showed in table 2 there were pretest-posttest design to compare the ejection fraction and increasing of ejection fraction between baseline and quality of life measurements before and after the adding of three months after the adding of Bisoprolol in most Bisoprolol to ACE inhibitor and furosemide combination for of patients. Wilcoxon test indicated that EF mean three months at stage C systolic heart failure patients. Before were significantly difference by 95% confidence of the adding of Bisoprolol, the patients should had accepted an interval (P = 0.000). This incline trend may indicated optimum dose of ACE inhibitor in order to ensure that the the role of Bisoprolol in increasing left ventricular improvements of left ventricular function was obtained by the function by decreasing heart rate and promoting adding of Bisoprolol to the combination of ACE inhibitor and adequate fil ing phase in the left ventricle. furosemide diuretic, since those combination had been proven to decrease heart failure morbidity and increase left Heart failure condition has very high impact on the ventricular ejection fraction based on the research conducted quality of life and should be examined frequently in by Simon and Nishio at 2002 and 2008 respectively12,13. order to predicted the worsening or improving left Systolic heart failure condition usual y accompanied by left ventricular function. The level of heart failure impact ventricular hypertrophy. The left ventricular fil ing wil be on the quality of life usual y measured by Minessota disturbed in the left ventricular hypertrophy condition. So that questionnaire which is contain twenty one questions the cardiac afterload volume decrease then aggravated by the each determines the frequencies of symptoms or reduction of the left ventricular myocyte contraction. All of the heart failure impact on phsycosocial life. The this condition bring to the reduction of cardiac output and more heart failure impact on the quality of life, the hypoperfusion through al of the body thus change the cel ular higher score were determined. The avarage of metabolism in to anaerob metabolism. This anaerob baseline and endpoint total scores for Minnesota metabolism will lead to clinical manifestation such as fatigue Living with Heart Failure questionnaire in patients due to lactic acid accumulation and this may lead to metabolic then compared by paired t test analysis since data acidosis. Left ventricular function has important role in the clinical manifestation in heart failure condition. Paired t test analysis showed there were significantly Ejection fraction describe the left ventricular function by difference in the score of Minnesota Living with measuring the fraction of the blood that ejected from the left Heart Failure questionnaire before and after the ventricle. Ejection fraction may be derivated by this formula: adding of Bisoprolol by 95% confidence of interval (P = 0.000). The total score of Minnesota Living with Heart Failure questionnaire tend to decrease after the adding of Bisoprolol to ACE inhibitor and A higher EF value means a higher blood fraction which is furosemide for three months. This indicated that the ejected from the left ventricle and by the reversed the lower routine adding of Bisoprolol to the combination of EF value means a lower blood fraction which is ejected from ACE inhibitor and furosemide may improved the the left ventricle and the worse left ventricular function. The quality of life in heart failure patients. reduction of cardiac output volume (EDV – ESV) due to impairment of the left ventricular ejection induce the This study limitation was the ignorance of the ACE increasing of blood volume which is left in the left ventricle inhibitor and furosemide to the improvement of ejection fraction and quality of life since previous International Journal of Pharmacy Teaching & Practices 2012, Vol.3, Issue 4, 429-433. study noted that those combination also improve left 9. Lechat, P., 1994. A Randomized Trial of β- ventricular function in heart failure. This study also consider Blockade in Heart Failure: The Cardiac Insufficiency that dose variation do not take important role in improving left Bisoprolol Study (CIBIS). Am Heart J. Vol. 90. pp 10. Lechat, P., Hulot, J.S., Escolano, S., Mal et, A., Further studies are needed to examine the role of dose Leizorovics, A., Werhlen-Grandjean, M., Pochmalicki, variation in heart failure therapy to the left ventricular G., Dargie, H., 2001. Heart Rate and Cardiac Rhythm improvement. Better study design such as randomized control Relationships With Bisoprolol Benefit in Chronic trial with the bigger sample size is needed to confirm our Heart Failure in CIBIS II Trial. Am Heart J. Vol. 103. results. As β-blocker monotherapy is not recommended in heart failure condition, so that the single effect of β-blocker on 11. Lee, D.S., et. al., 2009. Relation of Disease the left ventricular function is infeasible to be examined. Pathogenesis and Risk Factors to Heart Failure With Preserved or Reduced Ejection Fraction: Insights Conclusion
From the Framingham Heart Study of the National Heart, Lung, and Blood Institute. Am Heart J. Vol. Result of this prospective study showed that the routine addition of Bisoprolol to ACE inhibitor and furosemide 12. Nishio, M., Sakata, Y., Mano, T., Ohtani, T., combination may increase ejection fraction significantly by P = Takeda, Y., Miwa, T., Hori, M., Masuyama, T., Kondo, 0.000 and 95% confidence of interval. Bisoprolol addition to T., Yamamoto, K., 2008. Beneficial Effect of ACE inhibitor and furosemide combination may also improve Bisoprolol on The survival of Hypertensive Heart quality of life in systolic heart failure patients significantly (P = Failure. Eur J of Heart Failure. Vol. 10. pp 446-453 0.000 ; 95% confidence of interval) if measured by Minnesota 13. Simon, T., Mary-Krause, M., Funch-Brentano, C., Living with Heart Failure questionnaire. Lechat, P., Jail on, P., on behalf of CIBIS II Investigators, 2002. Bisoprolol Dose-Response Acknowledgement
Relationship in Patients with Congestive Heart Failure: A Subgroup Analysis in The Cardiac We are grateful to Research Development Unit, Medical Insufficiency Bisoprolol Study (CIBIS II). Eur Heart J. Faculty, Brawijaya University, Education Ministry of Indonesia and Dr Saiful Anwar General Hospital for facilitating this study. 14. Silvestry, F.E., et.al. 2009. Echocardiography- We also thank Diana Lyrawati, MSi., PhD for her Guided Interventions. USA: American Society of encouragement and valuable advice in publishing this 15. Tendera, M., 2004. The Epidemiology of Heart Failure. J RAA Syst. Vol. 5 (Suppl 1), pp. S2-S6. References
1. Abraham, W.T., 2000. β-Blockers The New Standar of Therapy for Mild Heart Failure. Arch Intern Med, Vol. 160, pp. 1237-1247 AUTHORS’ CONTRIBUTIONS
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